An antiretroviral (ARV) regimen for a treatment-naive patient generally consists of two nucleoside reverse transcriptase inhibitors (NRTIs) in combination with a third active ARV drug from one of three drug classes: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) with a pharmacokinetic (PK) enhancer (booster) (cobicistat or ritonavir).

The Panel on Antiretroviral Guidelines for Adults and Adolescents (the Panel) classifies the following regimens as Recommended Initial Regimens for Most People with HIV (in alphabetical order):

Dolutegravir/abacavir/lamivudinea—only for patients who are HLA-B*5701-negative (AI)

To address individual patient characteristics and needs, the Panel also provides a list of Recommended Initial Regimens in Certain Clinical Situations (Table 6).

Given the many excellent options for initial therapy, selection of a regimen for a particular patient should be guided by factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance testing results, comorbid conditions, access, and cost. Table 7 provides guidance on choosing an ARV regimen based on selected clinical case scenarios. Table 8 highlights the advantages and disadvantages of different components in a regimen.

a Lamivudine may substitute for emtricitabine or vice versa.b Tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are two forms of tenofovir approved by the Food and Drug Administration. TAF has fewer bone and kidney toxicities than TDF, while TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs.

Introduction

More than 25 antiretroviral (ARV) drugs in six mechanistic classes are Food and Drug Administration (FDA)-approved for treatment of HIV infection. These six classes include the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), a fusion inhibitor (FI), a CCR5 antagonist, and integrase strand transfer inhibitors (INSTIs). In addition, two drugs, ritonavir (RTV or r) and cobicistat (COBI or c) are used solely as pharmacokinetic (PK) enhancers (or boosters) to improve the PK profiles of some ARV drugs (e.g., PIs and the INSTI elvitegravir [EVG]).

The initial ARV regimen for a treatment-naive patient generally consists of two NRTIs, usually abacavir/lamivudine (ABC/3TC) or either tenofovir alafenamide (TAF)/emtricitabine (FTC) or tenofovir disoproxil fumarate (TDF)/FTC, plus a drug from one of three drug classes: an INSTI, an NNRTI, or a PK-enhanced PI. As shown in clinical trials and by retrospective evaluation of cohorts of patients in clinical care, this strategy for initial treatment has resulted in suppression of HIV replication and CD4 T lymphocyte (CD4) cell increases in most persons with HIV.1-3

Supporting Evidence and Rationale Used for Panel’s Recommendations

The Panel on Antiretroviral Guidelines for Adults and Adolescents (the Panel)’s recommendations are primarily based on clinical trial data published in peer-reviewed journals and data prepared by manufacturers for FDA review. In select cases, the Panel considers data from abstracts presented at major scientific meetings. The Panel considers published information from a randomized, prospective clinical trial with an adequate sample size that demonstrates that an ARV regimen produces high rates of viral suppression, increases CD4 count, and has a favorable safety profile to be the strongest evidence on which to base recommendations. Comparative clinical trials of initial treatments generally show no significant differences in HIV-related clinical endpoints or survival. Thus, assessment of regimen efficacy and safety are primarily based on surrogate marker endpoints (especially rates of HIV RNA suppression) and the incidence and severity of adverse events.

In some instances, the Panel recommends regimens that include medications approved by the FDA based on bioequivalence or relative bioavailability studies demonstrating that the exposure of the drug(s) in the new formulation or combination is comparable to the exposure of a reference drug(s) that has demonstrated safety and efficacy in randomized clinical trials. When developing recommendations, the Panel may also consider data from randomized switch studies in which a new medication replaces an existing medication from the same class in patients who have achieved virologic suppression on an initial regimen. Switch trials do not evaluate the ability of a drug or regimen to induce viral suppression; they only examine the drug or regimen’s ability to maintain suppression. Therefore, results from switch trials may not be directly applicable to the selection of an initial regimen and should be considered in conjunction with other data, including from trials conducted in treatment-naive patients and bioequivalence/bioavailability studies. In this section of the guidelines, the definition of an evidence rating of II is expanded to include supporting data from bioavailability/bioequivalence studies or randomized switch studies.

When developing recommendations, the Panel also considers tolerability and toxicity profiles, pill burden and dosing frequency, post-marketing safety data, observational cohort data published in peer-reviewed publications, and the experience of clinicians and community members who are actively engaged in patient care.

The Panel reviewed the available data to arrive at two regimen classifications for ARV-naive patients: (1) Recommended Initial Regimens for Most People with HIV and (2) Recommended Initial Regimens in Certain Clinical Situations (Table 6). Recommended Initial Regimens for Most People with HIV are those regimens with demonstrated durable virologic efficacy, favorable tolerability and toxicity profiles, and ease of use. The Panel also recognizes that, in certain clinical situations, other regimens may be preferred; these options are included in Table 6 in the category of Recommended Initial Regimens in Certain Clinical Situations. Examples of clinical scenarios in which certain drugs in these regimens may be particularly advantageous are outlined in Table 7.

There are many other ARV regimens that are effective for initial therapy, but have disadvantages compared with the regimens listed in Table 6. These disadvantages include greater toxicity, higher pill burden, less supporting data from large comparative clinical trials, or limitations for use in certain patient populations. These other regimens are no longer included in Table 6. A person with HIV who is virologically suppressed and who is not experiencing any adverse effects on a regimen that is not listed in Table 6 need not necessarily change to a regimen that is in that table.

Regimens and medications listed in Table 9 are not recommended. In most instances, a clinician is urged to consider switching a patient who is on one of the regimens listed in Table 9 to a recommended regimen.

In addition to these tables, a number of tables presented below and at the end of the Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV (Adult and Adolescent Guidelines) provide clinicians with guidance on selecting and prescribing an optimal regimen for an individual patient. Table 8 lists the potential advantages and disadvantages of the different antiretroviral drug components. Appendix B, Tables 1–6 lists characteristics of individual ARV agents (e.g., formulations, dosing recommendations, PKs, common adverse effects). Appendix B, Table 7 provides ARV dosing recommendations for patients who have renal or hepatic insufficiency.

Changes Since the Last Revision of the Guidelines

Since the last revision of the Adult and Adolescent Guidelines, there have been several important changes in the Panel’s recommendations for initial therapy of people with HIV. Among these changes, the following deserve emphasis:

INSTI-based regimens are recommended as initial therapy for most people with HIV. In large clinical trials and in clinical practice, INSTI-based regimens have achieved high rates of virologic suppression and often have greater tolerability than PI- or NNRTI-based regimens.

In certain clinical situations, a PI- or an NNRTI-based regimen may be preferred. In recognition of these situations, a new category—called Recommended Initial Regimens in Certain Clinical Situations—has been added to the Guidelines.

Darunavir (DRV)-based regimens have been moved to the category of Recommended Initial Regimens in Certain Clinical Situations based on trials showing improved outcomes with INSTI-based regimens when compared with ritonavir-boosted darunavir (DRV/r), in part because of greater tolerability of the former. An example of a situation in which a DRV-based regimen may still be preferred is when a high genetic barrier to resistance is particularly important, such as when there is substantial concern regarding a person’s adherence or when antiretroviral therapy (ART) should be initiated before resistance test results are available. Other examples of important clinical considerations that may favor specific regimens are included in Table 7.

Recommended NRTI combinations continue to be ABC/3TC and one of the tenofovir products—TAF or TDF—with FTC. With additional data since the last revision, the relative advantages of the two available tenofovir formulations have become clearer. TAF has less bone and kidney toxicity than TDF and is therefore particularly advantageous in people with underlying bone and kidney disease or those at high risk for these conditions. TDF is associated with lower lipid levels than TAF, perhaps because TDF results in higher plasma levels of tenofovir, which lowers lipids. Safety, cost, and access are among the factors to consider in choosing between these two formulations of tenofovir. Guidance for the clinician on choosing between ABC-, TAF-, and TDF-containing regimens are featured in these guidelines.

Table 6. Recommended Antiretroviral Regimens for Initial Therapy

Selection of a regimen should be individualized based on virologic efficacy, potential adverse effects, pill burden, dosing frequency, drug-drug interaction potential, comorbid conditions, cost, access, and resistance test results. Drug classes and regimens within each class are arranged first by evidence rating, and, when ratings are equal, in alphabetical order. Table 7 provides ARV recommendations based on specific clinical scenarios.

Recommended regimens are those with demonstrated durable virologic efficacy, favorable tolerability and toxicity profiles, and ease of use.

INSTI + 2 NRTIs:

DTG/ABC/3TCa(AI)—if HLA-B*5701 negative

DTG + tenofovirb/FTCa (AI for both TAF/FTC and TDF/FTC)

EVG/c/tenofovirb/FTC (AI for both TAF/FTC and TDF/FTC)

RALc + tenofovirb/FTCa (AI for TDF/FTC, AII for TAF/FTC)

Recommended Initial Regimens in Certain Clinical Situations

These regimens are effective and tolerable, but have some disadvantages when compared with the regimens listed above, or have less supporting data from randomized clinical trials. However, in certain clinical situations, one of these regimens may be preferred (see Table 7 for examples).

a 3TC may be substituted for FTC, or vice versa, if a non–fixed-dose NRTI combination is desired.b TAF and TDF are two forms of tenofovir approved by the FDA. TAF has fewer bone and kidney toxicities than TDF, while TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs.c RAL can be given as 400 mg BID or 1200 mg (two 600-mg tablets) once daily.d Several other NRTI-limiting treatment strategies are under investigation. See the section titled Selected Strategies That Are Under Evaluation and Not Yet Recommended below for discussion regarding these regimens. e LPV/r plus 3TC is the only boosted PI plus 3TC regimen with published 48-week data in a randomized controlled trial in ART-naive patients. Limitations of LPV/r plus 3TC include twice-daily dosing, high pill burden, and greater rates of gastrointestinal side effects than other PIs.

Initial therapy generally consists of two NRTIs combined with an INSTI, an NNRTI, or a PK-enhanced PI.

Choosing the Two Nucleoside Reverse Transcriptase Inhibitors

All the Recommended Initial Regimens for Most People with HIV and most of the Recommended Initial Regimens in Certain Clinical Situations include an NRTI combination of ABC/3TC, TAF/FTC, or TDF/FTC, each of which is available as a fixed-dose combination tablet. The choice of NRTI combination is usually guided by differences between ABC, TAF, and TDF, because FTC and 3TC have few adverse events and comparable efficacy. The main advantages of TAF and TDF over ABC are their activity against hepatitis B virus (HBV) and the fact that HLA-B*5701 testing is not required for their use. Moreover, TDF has been associated with lower lipid levels than TAF and ABC. However, TDF use has been associated with declines in kidney function, proximal renal tubulopathy (leading to proteinuria and phosphate wasting), and reductions in bone mineral density (BMD). These tenofovir toxicities are less common with TAF, which results in lower plasma tenofovir concentrations than TDF. As a result, the main advantages of TAF over TDF are TAF’s more favorable effects on renal markers and BMD.4-6 The main advantages of ABC over TDF are that it does not require dose adjustment in patients with renal insufficiency and has less nephrotoxicity and less deleterious effects on BMD than TDF. However, ABC use has been linked to cardiovascular events in some, but not all, observational studies. Considerations germane to the choice between TAF, TDF, and ABC in specific clinical scenarios are summarized in Table 7, Table 8, and in the section on dual-NRTI options below. For patients in whom ABC, TAF, or TDF cannot be used, recommendations for NRTI-limiting treatment regimens are given in Table 6 and in the section below on Other Antiretroviral Regimens for Initial Therapy When Abacavir, Tenofovir Alafenamide, and Tenofovir Disoproxil Fumarate Cannot Be Used.

Choosing Between an INSTI-, PI-, or NNRTI-Based Regimen

The choice between an INSTI, PI, or NNRTI as the third drug in an initial ARV regimen should be guided by the regimen’s efficacy, genetic barrier to resistance, adverse effects profile, and convenience. The patient’s comorbidities, concomitant medications, and the potential for drug-drug interactions should also be considered (see Tables 7 and 8 for guidance). The Panel’s Recommended Initial Regimens for Most People with HIV as listed in Table 6 include an INSTI plus two NRTIs. For most patients, an INSTI-containing regimen will be highly effective, have few adverse effects, and (with raltegravir [RAL] and dolutegravir [DTG]) have no significant CYP3A4-associated drug interactions. In addition, in several head-to-head comparisons between boosted PI- and INSTI-containing regimens, the INSTI was better tolerated with fewer treatment discontinuations.7-9 For these reasons, all three currently available INSTIs are included among the Recommended Initial Regimens for Most People with HIV. An exception is in those individuals with uncertain adherence or in whom treatment needs to begin before resistance testing results are available (e.g., during acute HIV infection, pregnancy, and in the setting of certain opportunistic infections). In this context, DRV/r may have an important role given the low rate of transmitted PI resistance, its high genetic barrier to resistance, and low rate of treatment-emergent resistance during many years of clinical experience. DTG may also be considered for patients who must start ART before resistance testing results are available. Because of its high barrier to resistance, DTG resistance is uncommon in patients experiencing virologic failure while on a DTG-containing initial regimen, and transmitted resistance has not yet been identified. Ritonavir-boosted atazanavir (ATV/r) has demonstrated excellent virologic efficacy in clinical trials and has relatively few metabolic adverse effects in comparison to other boosted-PI regimens; however, a randomized clinical trial showed that ATV/r had a higher rate of adverse effect-associated drug discontinuation than DRV/r and RAL.7 In a substudy of this same trial, and in a separate cross-sectional cohort study, ATV/r use was associated with less progression of atherosclerosis as measured by carotid artery intima medial thickness.10,11 Whether this finding will translate into a clinical benefit is uncertain. Large observational cohorts found an association between some PIs (DRV/r, fosamprenavir [FPV], indinavir [IDV], and ritonavir-boosted lopinavir [LPV/r]) and an increased risk of cardiovascular events, while this association was not seen with ATV.12-15 Another observational cohort of predominantly male participants showed a lower rate of cardiovascular events in participants receiving ATV-containing regimens compared with other regimens.16 Further study is needed.

NNRTI-based (efavirenz [EFV] or rilpivirine [RPV]) regimens may be optimal choices for some patients, although these drugs have low genetic barriers to resistance. EFV has a long track record of widespread use in the United States and globally, and its minimal PK interaction with rifamycins makes it an attractive option for patients who require concomitant treatment for tuberculosis (TB). Most EFV-based regimens have excellent virologic efficacy, including in patients with high HIV RNA (except when EFV is used with ABC/3TC); however, the relatively high rate of central nervous system (CNS)-related side effects makes EFV-based regimens less tolerable than other regimens. RPV has fewer adverse effects than EFV, is available as one of the smallest coformulated single tablets, and has a favorable lipid profile. However, RPV has lower virologic efficacy in patients with high baseline HIV RNA (>100,000 copies/mL) and low CD4 count (<200 cells/mm3).

Factors to Consider When Selecting an Initial Regimen

When selecting a regimen for an individual person with HIV, a number of patient- and regimen-specific characteristics should be considered. The goal is to provide a potent, safe, tolerable, and easy-to-adhere-to regimen for the patient in order to achieve sustained virologic control. Some of the factors can be grouped into the following categories:

Initial Characteristics to Consider in All Persons with HIV:

Pretreatment HIV RNA level (viral load)

Pretreatment CD4 count

HIV genotypic drug resistance testing results (based on current rates of transmitted drug resistance to different ARV medications, standard genotypic drug-resistance testing in ARV-naive persons should focus on testing for mutations in the reverse transcriptase [RT] and protease [PR] genes. If transmitted INSTI resistance is a concern, providers should consider also testing for resistance mutations to this class of drugs).

Pregnancy or pregnancy potential. Clinicians should refer to the latest Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in The United States (Perinatal Guidelines) for more detailed recommendations on the safety and effectiveness of ARV drugs during pregnancy.

This table is designed to guide clinicians in choosing an initial ARV regimen according to various patient and regimen characteristics and specific clinical scenarios. When more than one scenario applies to a person with HIV, clinicians should review considerations for each relevant scenario and use their clinical judgment to select the most appropriate regimen. This table is intended to guide the initial choice of regimen. However, if a person is doing well on a particular regimen, it is not necessary to switch to another regimen based on the scenarios outlined in this table. Please see Table 8 for additional information regarding the advantages and disadvantages of particular ARV medications.

Patients with cirrhosis should be carefully evaluated by an expert in advanced liver disease.

Osteoporosis

Avoid TDF.

Use ABC or TAF.

ABC may be used if HLA-B*5701–negative. If HIV RNA >100,000 copies/mL, do not use ABC/3TC + (EFV or ATV/r).

TDF is associated with decreases in bone mineral density along with renal tubulopathy, urine phosphate wasting, and resultant osteomalacia. TAF and ABC are associated with smaller declines in bone mineral density than TDF.

Psychiatric illnesses

Consider avoiding EFV- and RPV-based regimens.

Patients on INSTI-based regimens with pre-existing psychiatric conditions should be closely monitored.

EFV and RPV can exacerbate psychiatric symptoms and may be associated with suicidality.

INSTIs have been associated with adverse neuropsychiatric effects in some retrospective cohort studies and case series.

EFV reduces methadone concentrations and may lead to withdrawal symptoms.

High cardiac risk

DTG-, RAL- or RPV-based regimens may be advantageous in this setting.

Consider avoiding ABC- and LPV/r -based regimens.

If a boosted PI is the desired option, an ATV-based regimen may have advantages over a DRV-based regimen.

An increased CV risk has been observed in some studies.

Observational cohort studies reported an association between some PIs (DRV, IDV, FPV, and LPV/r) and an increased risk of CV events, while this has not been seen with ATV (see text); further study is needed.

Cardiac QTc interval prolongation

Consider avoiding EFV- or RPV-based regimens if taking other medications with known risk of torsades de pointes, or in patients at higher risk of torsades de pointes.

High EFV or RPV concentrations may cause QT prolongation.

Hyperlipidemia

The Following ARV Drugs Have Been Associated with Dyslipidemia:

PI/r or PI/c

EFV

EVG/c

DTG, RAL, and RPV have fewer lipid effects.

TDF has been associated with lower lipid levels than ABC or TAF.

Patients with history of poor adherence to ARV or inconsistent engagement in care

For treatment of HBV, use FTC or 3TC with entecavir and a suppressive ART regimen (see HBV/HIV Coinfection).

TDF, TAF, FTC, and 3TC are active against both HIV and HBV. 3TC- or FTC-associated HBV mutations can emerge rapidly when these drugs are used without another drug active against HBV.

HCV treatment required

Refer to recommendations in HCV/HIV Coinfection, with special attention to potential interactions between ARV drugs and HCV drugs.

Treating TB disease with rifamycins

TAF is not recommended with any rifamycin-containing regimen.

If Rifampin is Used:

EFV can be used without dosage adjustment.

If RAL is used, increase RAL dose to 800 mg BID.

Use DTG at 50 mg BID dose only in patients without selected INSTI mutations (refer to product label).

If using a PI-based regimen, rifabutin should be used in place of rifampin in the TB regimen.

Rifamycins may significantly reduce TAF exposure.

Rifampin is a strong inducer of CYP3A4 and UGT1A1 enzymes, causing significant decrease in concentrations of PIs, INSTIs, and RPV.

Rifampin has a less significant effect on EFV concentration than on other NNRTIs, PIs, and INSTIs.

Rifabutin is a less potent inducer and is an option for patients receiving non-EFV-based regimens.

Refer to Tables 18a, b, d and e for dosing recommendations for rifamycins used with different ARV agents.

a TAF and TDF are two approved forms of tenofovir. TAF has less bone and kidney toxicities than TDF, whereas TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs.

The sections below provide clinicians with comparisons of different, currently recommended ARV drugs within a drug class. These comparisons include information related to the safety and virologic efficacy of different drugs based on clinical trial results and/or post-marketing data, specific factors to consider, and the rationales for the Panel’s recommendations.

ABC/3TC, TAF/FTC, and TDF/FTC are NRTI combinations recommended for use as components of initial therapy. Table 6 provides recommendations and ratings for the individual regimens. These recommendations are based on the virologic potency and durability, short- and long-term toxicity, and dosing convenience of these drugs. TAF and TDF are two approved forms of tenofovir. TAF has less bone and kidney toxicities than TDF, while TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs.

Clinical Trials Comparing Nucleoside Reverse Transcriptase Inhibitors

Abacavir/Lamivudine Compared to Tenofovir Disoproxil Fumarate/Emtricitabine
Several randomized controlled trials in ART-naive participants compared ABC/3TC to TDF/FTC, either with the same17-19 or a different (third) ARV drug (also see the discussion in the dolutegravir section).20

The ACTG 5202 study, a randomized controlled trial in more than 1,800 participants, evaluated the efficacy and safety of ABC/3TC and TDF/FTC when each was used in combination with either EFV or ATV/r.

Treatment randomization was stratified on the basis of a screening HIV RNA level <100,000 copies/mL or ≥100,000 copies/mL. HLA-B*5701 testing was not required before study entry.

A Data Safety Monitoring Board recommended early termination of the ≥100,000 copies/mL stratification group because of a significantly shorter time to study-defined virologic failure in the ABC/3TC arm than in the TDF/FTC arm.17 This difference in time to virologic failure between the arms was observed regardless of whether the third active drug was EFV or ATV/r.

There was no difference in time to virologic failure between ABC/3TC and TDF/FTC for participants who had plasma HIV RNA <100,000 copies/mL at screening.21

The ASSERT study compared open-label ABC/3TC with TDF/FTC in 385 HLA-B*5701–negative, ART-naive patients; all participants also received EFV. The primary study endpoint was renal safety of the regimens. At week 48, the proportion of participants with HIV RNA <50 copies/mL was lower among ABC/3TC-treated participants than among TDF/FTC-treated participants.18

In the HEAT study, 688 participants received ABC/3TC or TDF/FTC in combination with once-daily LPV/r. Virologic efficacy was similar in the two study arms. In a subgroup analysis of patients with baseline HIV RNA ≥100,000 copies/mL, the proportion of participants who achieved HIV RNA <50 copies/mL at 96 weeks did not differ between the two regimens.19

At 48 weeks, 92% of participants randomized to receive TAF and 90% of those randomized to receive TDF achieved plasma HIV RNA <50 copies/mL, demonstrating that TAF was noninferior to TDF when combined with EVG/c/FTC. Both regimens were well-tolerated. The studies did not have adequate power to assess whether renal failure and fracture rates were different between the TAF and TDF groups.4 At 144 weeks, TAF/FTC was superior to TDF/FTC (84.2% vs. 80% of participants achieved plasma HIV RNA <50 copies/mL, respectively), largely driven by a higher rate of treatment discontinuation in the TDF arm.22

Participants in the TAF arm had significantly smaller reductions in BMD at the spine and the hip than those in the TDF arm through 144 weeks.22

Through 96 weeks, change from baseline eGFR and renal biomarkers favored EVG/c/TAF/FTC, and renal tubular function was less affected by the EVG/c/TAF/FTC regimen than by the EVG/c/TDF/FTC regimen. Clinically significant renal events, including discontinuations for renal adverse events, were less frequent in participants receiving EVG/c/TAF/FTC than in those treated with EVG/c/TDF/FTC.23 A subset analysis of patients at high risk for chronic kidney disease showed a lower rate of at least 25% decline in eGFR in patients on EVG/c/TAF/FTC, compared to patients on EVG/c/TDF/FTC (11.5% vs. 24.9%, P < 0.001).6

Fasting lipid levels, including low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides, increased more in the TAF group than in the TDF group at 96 weeks, with no change in total cholesterol to HDL ratio.24

A phase 2 study of coformulated cobicistat-boosted DRV (DRV/c) plus TAF/FTC versus DRV/c plus TDF/FTC demonstrated similar virologic suppression rates in both arms (75% vs. 74%) in treatment-naive patients.25 Less proteinuria and less change in BMD were observed in the TAF arm.

Combination TAF/FTC was also approved based on efficacy and safety data from one switch study in virologically suppressed patients.5 This study included 663 patients with HIV RNA <50 copies/mL for at least 6 months on a regimen containing TDF/FTC. Participants were randomized to continue TDF/FTC or switch to TAF/FTC.

At 48 weeks, TAF/FTC was noninferior to TDF/FTC in that viral suppression was maintained by 94.3% and 93% of the participants, respectively.

Improvement in eGFR and renal biomarkers was more frequent in those switched to TAF/FTC. BMD improved in those switched to TAF/FTC but declined in those continuing on TDF/FTC.

Fasting lipid levels increased more in those who switched to TAF/FTC than in those who continued TDF/FTC.

To assess the ability of TAF to maintain HIV and HBV suppression, 72 patients with HIV/HBV coinfection who had HIV RNA <50 copies/mL and HBV DNA <9 log10 IU/mL on a stable regimen were switched to EVG/c/TAF/FTC.26 In this study, 96% of participants were on a TDF/FTC-containing regimen prior to the switch.

Those who switched to EVG/c/TAF/FTC maintained HIV suppression: 94.4% and 91.7% of participants at 24 and 48 weeks, respectively. At 24 and 48 weeks, 86.1% and 91.7% of participants had HBV DNA <29 log10 IU/mL.

Decreases in markers of proximal tubular proteinuria and biomarkers of bone turnover were seen in those who switched to EVG/c/TAF/FTC.26

Abacavir/Lamivudine (ABC/3TC)
ABC plus 3TC has been studied in combination with EFV, several PIs, and DTG in ART-naive patients.20,27-29

Adverse EffectsHypersensitivity Reactions:

Clinically suspected hypersensitivity reactions (HSRs) were observed in 5% to 8% of individuals who started ABC in clinical trials conducted before the use of HLA-B*5701 testing. The risk of HSRs is highly associated with the presence of the HLA-B*5701 allele; approximately 50% of HLA-B*5701–positive patients will have an ABC-related HSR if given this drug.30,31 HLA-B*5701 testing should precede use of ABC. ABC should not be given to patients who test positive for HLA-B*5701 and, based on a positive test result, ABC hypersensitivity should be noted on a patient’s allergy list. Patients who are HLA-B*5701–negative are far less likely to experience an HSR, but they should be counseled about the symptoms of the reaction. Patients who discontinue ABC because of a suspected HSR should never be rechallenged, regardless of their HLA-B*5701 status.

Cardiovascular Risk:

An association between ABC use and myocardial infarction (MI) was first reported in the D:A:D study. This large, multinational, observational study group found that recent (i.e., within 6 months) or current use of ABC was associated with an increased risk of MI, particularly in participants with pre-existing cardiac risk factors.13,32

Since the D:A:D report, several studies have evaluated the relationship between ABC therapy and cardiovascular events. Some studies have found an association.33-40 Others, including an FDA meta-analysis of 26 randomized clinical trials that evaluated ABC, have not.12,41-44

No consensus has been reached on the association between ABC use and MI risk or the mechanism for such an association.

Other Factors and Considerations:

ABC/3TC is available as a coformulated tablet and as a coformulated single-tablet regimen with DTG.

ABC and 3TC are available separately and as a coformulated tablet in generic tablet formulations.

ABC does not cause renal dysfunction and can be used instead of TDF in patients with underlying renal dysfunction or in those who are at high risk for renal effects. No dosage adjustment is required in patients with renal dysfunction.

The Panel’s Recommendations:

ABC should only be prescribed for patients who are HLA-B*5701–negative.

On the basis of clinical trial safety and efficacy data, experience in clinical practice, and the availability of DTG/ABC/3TC as a fixed-dose combination, the Panel classifies DTG/ABC/3TC as a Recommended Initial Regimen for Most People with HIV (AI) (see discussion of DTG in this section regarding the clinical efficacy data for ABC/3TC plus DTG).

ABC/3TC use with EFV, ATV/r, ATV/c, DRV/c, DRV/r, or RAL is only recommended for patients with pretreatment HIV RNA <100,000 copies/mL. See Table 6 for more detailed recommendations on use of ABC/3TC with these drugs.

ABC should be used with caution or avoided in patients with known high cardiovascular risk.

Tenofovir Alafenamide/Emtricitabine (TAF/FTC)
TAF, an oral prodrug of tenofovir (TFV), is hydrolyzed to TFV in plasma and then converted to TFV-diphosphate (TFV-DP) intracellularly, where it exerts its activity as an NRTI. Unlike TDF, which readily converts to TFV in plasma after oral absorption, TAF remains relatively stable in plasma, resulting in lower plasma and higher intracellular TFV concentrations. After oral administration, TAF 25 mg resulted in plasma TFV concentrations that were 90% lower than those seen with TDF 300 mg. Intracellular TFV-DP concentrations, however, were substantially higher with TAF.

Adverse EffectsRenal and Bone Effects:

The potential for adverse kidney and bone effects is lower with TAF than with TDF. In randomized controlled trials that compared TAF and TDF in treatment-naive or virologically suppressed patients, TAF had more favorable effects on renal biomarkers and bone density than TDF (described below).

Lipid Effects:

In the randomized controlled trials in ART-naive patients, as well as in switch studies (described below), levels of LDL and HDL cholesterol and triglycerides were higher in patients receiving TAF than in patients receiving TDF. However, total cholesterol to HDL ratios did not differ between patients receiving TAF and TDF. The clinical significance of this finding is not clear.4-6

Other Factors and Considerations:

TAF/FTC is available in fixed-dose drug combinations with EVG/c or RPV, allowing the regimens to be administered as a single pill taken once daily with food.

Both TAF and FTC are active against HBV. In patients with HIV/HBV coinfection, TAF/FTC may be used as the NRTI pair of the ART regimen because the drugs have activity against both viruses (see HBV/HIV Coinfection).26

The Panel’s Recommendation:

On the basis of clinical trial safety and efficacy data, supportive bioequivalence data,45 and its availability as a component of various fixed-dose combinations, the Panel considers TAF/FTC a recommended NRTI combination for initial ART in most persons with HIV when prescribed with DTG (AI), EVG/c (AI), and RAL (AII).

Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC)
TDF, with either 3TC or FTC, has been studied in combination with EFV, RPV, several boosted PIs, EVG/c, RAL, and DTG in randomized clinical trials.46,47-55

Adverse EffectsRenal Effects:

New onset or worsening renal impairment has been associated with TDF use.56,57 Risk factors may include advanced HIV disease, longer treatment history, low body weight (especially in females)58 and pre-existing renal impairment.59 Concomitant use of a PK-enhanced regimen (with a PI or EVG) can increase TDF concentrations; studies have suggested a greater risk of renal dysfunction when TDF is used in these regimens. As previously noted, adverse effects on renal biomarkers such as proteinuria, especially tubular proteinuria, were more frequent with TDF than with TAF.57,59-63

Bone Effects:

While initiation of all NRTI-containing regimens has been associated with a decrease in BMD, the loss of BMD is greater with TDF-containing regimens. For example, in two randomized studies comparing TDF/FTC with ABC/3TC, participants receiving TDF/FTC experienced a significantly greater decline in BMD than ABC/3TC-treated participants.64,65 BMD generally stabilizes following an early decline after ART initiation. Loss of BMD with TDF is also greater than with TAF (see above).

Cases of osteomalacia associated with proximal renal tubulopathy have been reported with the use of TDF.66

Other Factors and Considerations:

TDF/FTC is available in fixed-dose drug combinations with EFV, EVG/c, and RPV, allowing the regimens to be administered as a single pill, taken once daily.

Both TDF and FTC are active against HBV. In patients with HIV/HBV coinfection, TDF/FTC may be used as the NRTI pair of the ART regimen because the drugs have activity against both viruses (also see HBV/HIV Coinfection section).

The Panel’s Recommendations:

On the basis of clinical trial safety and efficacy data, long-term experience in clinical practice, and the combination’s availability as a component of fixed dose formation drugs, the Panel considers TDF/FTC a Recommended NRTI combination for initial ART in most persons with HIV when combined with DTG, EVG/c, or RAL. See Table 6 for recommendations regarding use of TDF/FTC with other drugs.

TDF should be used with caution or avoided in patients with renal disease and osteoporosis.

Integrase Strand Transfer Inhibitor–Based Regimens

Summary

Three INSTIs—DTG, EVG, and RAL—are currently approved for ARV-naive patients with HIV. DTG and EVG are currently available as components of one-tablet, once-daily complete regimens: DTG is coformulated with ABC/3TC; EVG is coformulated with a PK enhancer (COBI) and TAF/FTC or TDF/FTC. All INSTIs are generally well tolerated, though there are reports of insomnia in some patients. Depression and suicidal ideation, primarily in patients with a history of psychiatric illnesses, have rarely been reported in patients receiving INSTI-based regimens. INSTI-based regimens are Recommended Initial Regimens for Most People with HIV.

Dolutegravir (DTG)
DTG is an INSTI with a higher genetic barrier to resistance than EVG or RAL. In treatment-naive patients, DTG is given once daily, with or without food.

Efficacy in Clinical Trials:
The efficacy of DTG in treatment-naive patients has been evaluated in several fully powered randomized controlled clinical trials. In these three trials, DTG-based regimens were noninferior or superior to a comparator INSTI-, NNRTI-, or PI-based regimen. The primary efficacy endpoint in these clinical trials was the proportion of participants with plasma HIV RNA <50 copies/mL.

The SPRING-2 trial compared DTG 50 mg once daily to RAL 400 mg twice daily. Each drug was administered in combination with an investigator-selected two-NRTI regimen, either ABC/3TC or TDF/FTC, to 822 participants. At week 96, DTG was noninferior to RAL.55

The SINGLE trial compared DTG 50 mg once daily plus ABC/3TC to EFV/TDF/FTC in 833 participants. At week 48, DTG was superior to EFV, primarily because the study treatment discontinuation rate was higher in the EFV arm than in the DTG arm.20 At week 144, DTG plus ABC/3TC remained superior to EFV/TDF/FTC.68

The FLAMINGO study, a randomized open-label clinical trial, compared DTG 50 mg once daily to DRV/r 800/100 mg once daily, each in combination with investigator-selected ABC/3TC or TDF/FTC. At week 48, DTG was superior to DRV/r because of the higher rate of discontinuation in the DRV/r arm.69,70 The difference in response rates favoring DTG was greater in patients with pretreatment HIV RNA levels >100,000 copies/mL. At week 96, DTG remained superior to DRV/r.71

The ARIA trial is an open-label, phase 3b randomized controlled trial, comparing the efficacy and safety of DTG/ABC/3TC to ATV/r plus TDF/FTC in ART-naive, nonpregnant women. At week 48, 82% of participants in the DTG group achieved HIV RNA viral loads <50 copies/mL compared with 71% in the ATV group (P = 0.005). The difference was driven by a lower rate of virologic nonresponse and fewer withdrawals due to adverse events in the DTG group.72

Adverse Effects:

DTG is generally well tolerated. The most common adverse reactions of moderate to severe intensity with an incidence ≥2% in the clinical trials were insomnia and headache. Cases of HSRs were reported in <1% of trial participants.

Case series of neuropsychiatric adverse events (sleep disturbances, depression, anxiety, suicidal ideation) associated with the initiation of DTG and RAL have been reported.73,74 Two observational cohort studies reported a higher frequency of neuropsychiatric adverse events leading to treatment discontinuation in patients receiving DTG than in patients receiving other INSTIs.75,76 However, analyses of data from large randomized controlled trials as well as a health care database demonstrated similar rates of neuropsychiatric adverse events with DTG-based regimens versus other ARV regimens,77 with neuropsychiatric events rarely leading to DTG discontinuation. Another report from the World Health Organization international pharmacovigilance database reported neuropsychiatric events with all approved INSTIs,78 and not only DTG. Further studies will be needed to precisely clarify the true incidence and implications of these neuropsychiatric events. A pathophysiologic mechanism for these neuropsychiatric adverse events has not been defined.

Other Factors and Considerations:

DTG decreases tubular secretion of creatinine without affecting glomerular function, with increases in serum creatinine observed within the first 4 weeks of treatment (mean increase in serum creatinine was 0.11 mg/dL after 48 weeks).

DTG absorption may be reduced when the ARV is coadministered with polyvalent cations (see Drug Interactions). DTG should be taken at least 2 hours before or 6 hours after cation-containing antacids or laxatives. Alternatively, DTG and supplements containing calcium or iron can be taken simultaneously with food.

Treatment-emergent mutations that confer DTG resistance have not been reported in patients receiving DTG as part of a three-drug regimen for initial therapy, which suggests that DTG has a higher genetic barrier to resistance than other INSTIs.

The Panel’s Recommendation:

On the basis of clinical trial data, the Panel categorizes DTG in combination with ABC/3TC (AI), TAF/FTC (AI), or TDF/FTC (AI) as a Recommended Initial Regimen for Most People with HIV.

Elvitegravir (EVG)
EVG is available as a component of two single-tablet regimens: EVG/c/TDF/FTC and EVG/c/TAF/FTC. COBI is a specific, potent CYP3A inhibitor that has no activity against HIV. It acts as a PK enhancer of EVG, which allows for once-daily dosing of the combination.

Efficacy in Clinical Trials:

The efficacy of EVG/c/TDF/FTC in ARV-naive participants has been evaluated in two randomized, double-blind active-controlled trials.

At 144 weeks, EVG/c/TDF/FTC was noninferior to fixed-dose EFV/TDF/FTC.79

EVG/c/TDF/FTC was also found to be noninferior to ATV/r plus TDF/FTC.80

In a randomized, blinded trial performed in women with HIV, EVG/c/TDF/FTC had superior efficacy when compared to ATV/r plus TDF/FTC, in part because of a lower rate of treatment discontinuation.9

The efficacy of EVG/c/TAF/FTC in ARV-naive participants has been evaluated in two randomized, double-blind controlled trials in adults with eGFR ≥50 mL/min.4,24

At 48 and 96 weeks, TAF was noninferior to TDF when both were combined with EVG/c/FTC, whereas EVG/c/TAF/FTC was superior to EVG/c/TDF/FTC at 144 weeks.22

Adverse Effects:

The most common adverse events reported with EVG/c/TDF/FTC were diarrhea, nausea, upper respiratory infection, and headache.79,80

The most common adverse events reported with EVG/c/TAF/FTC were nausea, diarrhea, headache, and fatigue.81

Neuropsychiatric adverse events have been reported in people receiving INSTIs (see discussion under DTG).

Other Factors and Considerations:

EVG is metabolized primarily by CYP3A enzymes; as a result, CYP3A inducers or inhibitors may alter EVG concentrations.

Because COBI inhibits CYP3A, it interacts with a number of medications that are metabolized by this enzyme (see Drug Interactions).82

COBI inhibits active tubular secretion of creatinine, resulting in increases in serum creatinine and a reduction in estimated CrCl without reducing glomerular function.83 Patients with a confirmed increase in serum creatinine greater than 0.4 mg/dL from baseline while taking EVG/c/TDF/FTC should be closely monitored and evaluated for evidence of TDF-related proximal renal tubulopathy.63

EVG/c/TDF/FTC is not recommended for patients with pretreatment estimated CrCl <70 mL/min.63

EVG/c/TAF/FTC is not recommended for patients with pretreatment estimated CrCl <30 mL/min.

At the time of virologic failure, INSTI-associated mutations were detected in some EVG/c/TDF/FTC-treated patients whose therapy failed.79,80 These mutations conferred cross-resistance to RAL, with most retaining susceptibility to DTG.

The Panel’s Recommendation:

On the basis of the above considerations, the Panel classifies EVG/c/TAF/FTC and EVG/c/TDF/FTC as Recommended Initial Regimens for Most People with HIV (AI). EVG/c/TAF/FTC should only be used in people with estimated CrCl ≥30 mL/min; EVG/c/TDF/FTC should only be used in people with estimated CrCl ≥70 mL/min.

Raltegravir (RAL)
RAL was the first INSTI approved for use in both ARV-naive and ARV-experienced patients.

The efficacy of RAL at a dose of 400 mg twice daily (with either TDF/FTC or ABC/3TC) as initial therapy was evaluated in two randomized, double-blind, controlled clinical trials, and a third open-label randomized trial.

STARTMRK compared RAL 400 mg twice daily to EFV 600 mg once daily, each in combination with TDF/FTC. RAL was noninferior to EFV at 48 weeks.51 RAL was superior to EFV at 4 and 5 years,54,84 in part because of more frequent discontinuations due to adverse events in the EFV group than in the RAL group.

The SPRING-2 trial compared DTG 50 mg once daily to RAL 400 mg twice daily, each in combination with investigator-selected ABC/3TC or TDF/FTC. At week 96, DTG was noninferior to RAL.

The SPRING-2 trial also provided nonrandomized data on the efficacy of RAL plus ABC/3TC. In this trial, 164 participants (39 and 125 participants with baseline viral loads ≥100,000 copies/mL and <100,000 copies/mL, respectively) received RAL in combination with ABC/3TC. After 96 weeks, there was no difference in virologic response between the ABC/3TC and TDF/FTC groups when RAL was given as the third drug.55

ACTG A5257, a large randomized open-label trial, compared three NNRTI-sparing regimens containing RAL, ATV/r, or DRV/r, each given with TDF/FTC. At week 96, all three regimens had similar virologic efficacy, but RAL was superior to both ATV/r and DRV/r for the combined endpoints of virologic efficacy and tolerability. Participants had greater increases in lipid levels in the ritonavir-boosted protease inhibitor (PI/r) arms than in the RAL arm, and BMD decreased to a greater extent in participants in the PI/r arms than in participants in the RAL arm.7

In a phase 3, randomized, double-blind, active comparator-controlled trial (the ONCEMRK trial), the efficacy of once-daily RAL 1200 mg (formulated as two 600-mg tablets) was compared to RAL 400 mg twice daily, each with TDF/FTC. At 96 weeks, a similar proportion of participants in both groups achieved HIV RNA suppression (81.5% in the once-daily arm vs. 80.1% in the twice-daily arm). The responses were similar regardless of baseline HIV RNA or CD4 count.85

Adverse Effects:

RAL use has been associated with creatine kinase elevations. Myositis and rhabdomyolysis have been reported.

Rare cases of severe skin reactions and systemic HSRs in patients who received RAL have been reported during post-marketing surveillance.86

RAL can be administered as 1200 mg (two 600-mg tablets) once a day or as 400 mg twice daily with or without food in ART-naive patients.

Coadministration of RAL as either 400 mg twice daily or 1200 mg once daily with aluminum- and/or magnesium-containing antacids is not recommended. Calcium carbonate-containing antacids may be coadministered with RAL 400 mg twice daily, but not with RAL 1,200 mg once daily. Polyvalent cation-containing supplements may also reduce absorption of RAL. See Table 18d for dosing recommendations.

RAL has a lower genetic barrier to resistance than RTV-boosted PIs and DTG.

The Panel’s Recommendations:

On the basis of these clinical trial data, the Panel considers RAL given as 1200 mg (two 600-mg tablets) once daily or as 400 mg twice daily plus TDF/FTC (AI) or TAF/FTC (AII) as a Recommended Initial Regimen for Most People with HIV.

Because fewer patients have received RAL plus ABC/3TC in clinical trials or practice and there has not been a randomized trial comparing ABC/3TC plus RAL to TDF/FTC plus RAL, the Panel categorizes RAL plus ABC/3TC as a Recommended Initial Regimen in Certain Clinical Situations (BII).

NNRTI-based regimens have demonstrated virologic potency and durability. The major disadvantages of currently available NNRTIs are the prevalence of NNRTI-resistant viral strains in ART-naive patients88 and the drugs’ low genetic barrier for the development of resistance. Resistance testing should be performed to guide therapy selection for ART-naive patients (see Drug-Resistance Testing). High-level resistance to all NNRTIs (except ETR) may occur with a single mutation; within-class cross-resistance is common. In RPV-treated patients, the presence of RPV resistance mutations at virologic failure may confer cross-resistance to other NNRTIs, including ETR.89,90 EFV- and RPV-based regimens are now categorized as Recommended Initial Regimens in Certain Clinical Situations for ART-naive patients for the following reasons:

Their low genetic barrier for resistance;

EFV is less well tolerated than the Recommended regimens; and

In a randomized controlled trial that compared RPV and EFV, the rate of virologic failure among participants with high pretreatment viral loads (>100,000 copies/mL) or low CD4 counts (<200 cells/mm3) was higher among the RPV-treated participants.

Efavirenz (EFV)

Efficacy in Clinical Trials:
Large randomized, controlled trials and cohort studies in ART-naive patients have demonstrated potent and durable viral suppression in patients treated with EFV plus two NRTIs. In clinical trials, EFV-based regimens in ART-naive patients have demonstrated superiority or noninferiority to several comparator regimens.

In ACTG 5202, EFV was comparable to ATV/r when each was given with either TDF/FTC or ABC/3TC.91

In the ECHO and THRIVE studies, EFV was noninferior to RPV, with less virologic failure. However, EFV caused more discontinuations due to adverse events. The virologic advantage of EFV was most notable in participants with pre-ART viral loads >100,000 copies/mL, and NRTI and NNRTI resistance was more frequent with RPV failure.92

In the GS 102 study, EFV/TDF/FTC was noninferior to EVG/c/TDF/FTC.79

Some regimens have demonstrated superiority to EFV, based primarily on fewer discontinuations because of adverse events:

In the SINGLE trial, a DTG-based regimen was superior to EFV at the primary endpoint of viral suppression at week 48.20

In the STARTMRK trial, RAL was noninferior to EFV at 48 weeks.51 RAL was superior to EFV at 4 and 5 years,54,84 in part because of more frequent discontinuations due to adverse events in the EFV group than in the RAL group.

In the open-label STaR trial, participants with baseline viral loads ≤100,000 copies/mL had higher rates of treatment success on RPV than on EFV.93

ENCORE 1, a multinational randomized placebo-controlled trial, compared two once-daily doses of EFV (combined with TDF/FTC): EFV 600 mg (standard dose) versus EFV 400 mg (reduced dose). At 96 weeks, EFV 400 mg was noninferior to EFV 600 mg for rate of viral suppression.94 Study drug-related adverse events were less frequent in the EFV 400 mg group than in the 600 mg group. Although there were fewer self-reported CNS events in the 400 mg group, the groups had similar rates of psychiatric events. Unlike the 600 mg dose of EFV, the 400 mg dose is not approved for initial treatment, it is not coformulated in a fixed-dose combination tablet, and data for its use in pregnancy and in patients with TB/HIV coinfection are lacking.

Adverse Effects:

EFV can cause CNS side effects (e.g., abnormal dreams, dizziness, headache, and depression), which resolve over a period of days to weeks in most patients. However, subtler, long-term neuropsychiatric effects can occur. An analysis of four AIDS Clinical Trial Group (ACTG) comparative trials showed a higher rate of suicidality (i.e., reported suicidal ideation or attempted or completed suicide) among EFV-treated patients than among patients taking comparator regimens.95 This association, however, was not found in analyses of three large observational cohorts,96,97 or in a retrospective cohort study that used U.S. administrative pharmacy claims data.98

EFV may cause elevation in LDL cholesterol and triglycerides.

QTc interval prolongation has been observed with EFV use.99,100 Consider an alternative therapy to EFV in patients taking medications known to increase the risk of torsades de pointes, or in patients at higher risk of torsades de pointes.

Other Factors and Considerations:

EFV is formulated both as a single-drug tablet and in a fixed-dose combination tablet of EFV/TDF/FTC that allows for once-daily dosing.

EFV is a substrate of CYP3A4 and an inducer of CYP3A4 and 2D6 and therefore may potentially interact with other drugs using the same pathways (see Tables 18b, 19a, and 19b).

EFV has been associated with CNS birth defects in nonhuman primates, and cases of neural tube defects have been reported after first trimester exposure in humans.101 A link between EFV and birth defects in humans has not been supported in meta-analyses (see the Perinatal Guidelines).102

Because EFV has been associated with depression and suicidality, screening for antenatal and postpartum depression in women with HIV who are taking a regimen that includes EFV is recommended.

The Panel’s Recommendations:

Given the availability of regimens with fewer treatment-limiting adverse events and also with noninferior or superior efficacy, the Panel classifies EFV/TDF/FTC (BI) or EFV plus TAF/FTC (BII) as Recommended Initial Regimens in Certain Clinical Situations.

EFV at a reduced dose has not been studied in the U.S. population, in pregnant women, or in patients with TB/HIV coinfection. The Panel cannot recommend the use of reduced-dose EFV.

Rilpivirine (RPV)

RPV is an NNRTI approved for use in combination with NRTIs for ART-naive patients with pretreatment viral loads <100,000 copies/mL.

Efficacy in Clinical Trials:
Two phase 3 randomized, double-blind clinical trials—ECHO and THRIVE—compared RPV and EFV, each combined with two NRTIs.92 At 96 weeks, the following findings were reported:

RPV was noninferior to EFV overall.

Among participants with a pre-ART viral load >100,000 copies/mL, more RPV-treated participants than EFV-treated participants experienced virologic failure. Moreover, in this subgroup of participants with virologic failure, NNRTI and NRTI resistance was more frequently identified in those treated with RPV.

Among the RPV-treated participants, the rate of virologic failure was greater in those with pretreatment CD4 counts <200 cells/mm3 than in those with CD4 counts ≥200 cells/mm3.

STaR, a phase 3b, open-label study, compared the fixed-dose combinations of RPV/TDF/FTC and EFV/TDF/FTC in 786 treatment-naive patients. The results at 96 weeks103 were similar to the findings reported at 48 weeks.93

RPV was noninferior to EFV overall.

RPV was superior to EFV in patients with pre-ART viral loads ≤100,000 copies/mL and noninferior in those with pre-ART viral loads >100,000 copies/mL. In patients with pre-ART viral loads >500,000 copies/mL, virologic failure was more common in RPV-treated patients than in EFV-treated patients.

There were more participants with emergent resistance in the RPV/FTC/TDF arm than in the EFV/FTC/TDF arm (4% vs. 1%, respectively).

The fixed-dose combination tablet of RPV/TAF/FTC was approved by the FDA based on results from a bioequivalence study. In this study, participants taking the coformulated drug had plasma concentrations of RPV, FTC, and TAF 25 mg that were similar to concentrations seen in participants who received RPV as the single-tablet formulation and TAF/FTC when given as part of the fixed-dose combination of EVG/c/TAF 10 mg/FTC.45

Adverse Effects:

RPV is generally well tolerated. In the ECHO, THRIVE, and STaR trials, fewer CNS adverse events (e.g., abnormal dreams, dizziness, psychiatric side effects), skin rash, and dyslipidemia were reported in the RPV arms than the EFV arms, and fewer patients in the RPV arms discontinued therapy due to adverse events. However, up to 9% of clinical trial participants experienced depressive disorders, including approximately 1% of participants who had suicidal thoughts or who attempted suicide. Patients with severe depressive symptoms should be evaluated to assess whether symptoms may be due to RPV and if the risks of continued treatment outweigh the benefits.

Other Factors and Considerations:

RPV is formulated both as a single-drug tablet and in fixed-dose combination tablets with TAF/FTC and with TDF/FTC. Among available single-tablet regimens, RPV/TAF/FTC is the smallest tablet.

RPV/TAF/FTC and RPV/TDF/FTC are given once daily, and must be administered with a meal (containing at least 390 kcal).

The oral drug absorption of RPV can be significantly reduced in the presence of acid-lowering agents. RPV is contraindicated in patients who are receiving proton pump inhibitors, and should be used with caution in those receiving H2 antagonists or antacids (see Drug Interactions for dosing recommendations).

RPV is primarily metabolized in the liver by the CYP3A enzyme; its plasma concentration may be affected in the presence of CYP3A inhibitors or inducers (see Drug Interactions).

At higher than the approved dose of 25 mg, RPV may cause QTc interval prolongation. RPV should be used with caution when coadministered with a drug known to increase the risk of torsades de pointes.

The Panel’s Recommendations:

Given the availability of other effective regimens that do not have virologic and immunologic prerequisites to initiate treatment, the Panel recommends RPV/TDF/FTC and RPV/TAF/FTC as Recommended Initial Regimens in Certain Clinical Situations.

Use of RPV with TAF/FTC (BII) or TDF/FTC (BI) should be limited to ART-naive patients with pretreatment viral load <100,000 copies/mL and CD4 count >200 cells/mm3.

Data on RPV plus ABC/3TC are insufficient to consider recommending this regimen.

Protease Inhibitor-Based Regimens

Summary

FDA-approved PIs include ATV, ATV/c, DRV, DRV/c, FPV, IDV, LPV/r, nelfinavir (NFV), RTV, saquinavir (SQV), and tipranavir (TPV). PI-based regimens with PK enhancement have demonstrated virologic potency, durability in treatment-naive patients, and a high genetic barrier to resistance. Few or no PI mutations are detected when a patient’s first PI-based regimen fails, which is not the case with NNRTI- and some INSTI-based regimens.104,105 For this reason, PI-based regimens may be useful for patients at risk for intermittent therapy due to poor adherence. All PIs (PK-enhanced by either RTV or COBI) inhibit the CYP3A4 isoenzyme, which may lead to significant drug-drug interactions (see Drug Interactions). Each PI has specific characteristics related to its virologic potency, adverse effects profile, and PK properties. The characteristics of Recommended PIs are listed in Table 8 and Appendix B, Table 3.

PIs that are recommended for use in ART-naive patients should have proven virologic efficacy, once-daily dosing, a low pill count, and good tolerability. On the basis of these criteria, the Panel considers once-daily DRV/r, DRV/c, ATV/c, or ATV/r together with two NRTIs as PI-based regimen options in the category of Recommended Initial Regimens in Certain Clinical Situations. In a large, randomized controlled trial comparing DRV/r, ATV/r, and RAL, all in combination with TDF/FTC, all three regimens achieved similar virologic suppression rates; however, the proportion of patients who discontinued their assigned treatment because of adverse effects, mainly hyperbilirubinemia, was greater in the ATV/r arm than in the other two arms.7

Several metabolic abnormalities, including dyslipidemia and insulin resistance, have been associated with PI use. The currently available PIs differ in their propensity to cause these metabolic complications, which also depends on the dose of RTV used as a PK-enhancing agent. Large observational cohort studies found an association between some PIs (i.e., DRV/r, FPV, IDV, and LPV/r) and an increased risk of cardiovascular events, while this was not seen with ATV.12-14,106 Another observational cohort study of predominantly male participants found a lower rate of cardiovascular events in those receiving ATV-containing regimens compared with other regimens.16 Further study is needed.

LPV/r has twice the daily dose of RTV as other PI/r regimens and is associated with more metabolic complications and gastrointestinal side effects than PK-enhanced ATV or DRV. The Panel no longer recommends LPV/r plus two NRTIs as a regimen for initial therapy, given the availability of other PIs coformulated with PK enhancers that can be given once daily and the accumulation of experience with other ART regimens with fewer toxicities. DRV/r plus twice daily RAL or LPV/r plus 3TC are regimens to be considered when ABC, TAF, or TDF cannot be used (see below). Compared to other PIs, FPV/r, unboosted ATV, and SQV/r have disadvantages such as greater pill burden, lower efficacy, or increased toxicity, and thus are not included as options for initial therapy.

Recommended Protease Inhibitor-Based Regimen

Darunavir/Ritonavir (DRV/r)

Efficacy in Clinical Trials:

The ARTEMIS study compared DRV/r (800/100 mg once daily) with LPV/r (800/200 mg once daily or 400/100 mg twice daily), both in combination with TDF/FTC, in a randomized, open-label, noninferiority trial. DRV/r was noninferior to LPV/r at week 48,49 and superior at week 192.107 Among participants with baseline HIV RNA levels >100,000 copies/mL, virologic response rates were lower in the LPV/r arm than in the DRV/r arm.

The FLAMINGO study compared DRV/r with DTG, each in combination with two NRTIs, in 488 ART-naive participants. The rate of virologic suppression at week 96 was significantly greater among those who received DTG than in those who received DRV/r. The excess failure observed in the DRV/r group was primarily related to a higher rate of virologic failure among those with a viral load >100,000 copies/mL and secondarily due to more drug discontinuations in the DRV/r group.8

ACTG A5257, a large randomized open-label trial, compared ATV/r with DRV/r or RAL, each given with TDF/FTC. The trial showed similar virologic efficacy for DRV/r, ATV/r, and RAL, but more participants in the ATV/r group discontinued randomized treatment because of adverse events.7

Adverse Effects:

Patients starting DRV/r may develop a skin rash, which is usually mild-to-moderately severe and self-limited.Treatment discontinuation is necessary on rare occasions when severe rash with fever or elevated transaminases occur.

ACTG A5257 showed similar lipid changes in participants in the ATV/r and DRV/r arms. BMD decreased to a greater extent in participants in the ATV/r and DRV/r arms than in participants in the RAL arm.7 The likelihood of developing metabolic syndrome was equivalent between the three arms, although a larger increase in waist circumference was observed in participants assigned to the RAL arm than in those in the DRV/r arm at 96 weeks (P ≤ 0.02).108

An observational cohort study suggested that DRV/r is associated with increased rates of cardiovascular disease.106

Other Factors and Considerations:

DRV/r is administered once daily with food in treatment-naive patients.

DRV has a sulfonamide moiety, and should be used with caution in patients with severe sulfonamide allergies. In clinical trials, the incidence and severity of rash were similar in participants who did or did not have a history of sulfonamide allergy. Most patients with sulfonamide allergy are able to tolerate DRV.

DRV/r is a potent CYP3A4 inhibitor, and may lead to significant interactions with other medications metabolized through this same pathway (see Drug Interactions).

The Panel’s Recommendations:

On the basis of efficacy and safety data from clinical trials and clinical experience, the Panel classifies DRV/r with TDF/FTC (AI), with TAF/FTC (AII), or with ABC/3TC (BII) as Recommended Initial Regimens in Certain Clinical Situations.

Darunavir/Cobicistat (DRV/c)
A combination of DRV 800 mg with COBI 150 mg is bioequivalent to DRV 800 mg with RTV 100 mg in healthy volunteers based on the maximum concentration and area under the concentration time curve for DRV.109 Because the minimum concentration (Cmin) of DRV combined with COBI was 31% lower than that with DRV combined with RTV, bioequivalence for the Cmin was not achieved.110

Efficacy in Clinical Trials:

In a single-arm trial of treatment-naive (94%) and treatment-experienced (6%) patients, the coformulated DRV/c 800/150 mg tablet was evaluated in combination with two investigator-selected NRTIs (99% of participants were given TDF/FTC). At week 48, 83% of treatment-naive participants achieved HIV RNA <50 copies/mL; 5% of participants discontinued treatment because of adverse events.111

A phase 2 study of coformulated DRV/c plus TAF/FTC versus DRV/c plus TDF/FTC demonstrated similar virologic suppression rates in both arms (75% and 74%, respectively) in treatment-naive patients.25 Less proteinuria and less change in bone mineral density were observed in the TAF arm.

Adverse Effects:

The most common treatment-emergent adverse events were diarrhea, nausea, fatigue, flatulence, rash, and headache.

An observational cohort study suggested that DRV/r is associated with increased rates of cardiovascular disease;106 data on DRV/c are too limited to draw conclusions.

Other Factors:

DRV 800 mg and COBI 150 mg is available as a coformulated tablet.

The Panel’s Recommendations:

On the basis of the bioequivalence study and the single-arm trial, the Panel recommends DRV/c plus TAF/FTC or TDF/FTC (BII) and DRV/c plus ABC/3TC (BIII) as Recommended Initial Regimens in Certain Clinical Situations.

DRV/c plus TDF/FTC is not recommended for patients with CrCl <70 mL/min, whereas DRV/c plus TAF/FTC is not recommended for patients with CrCl <30 mL/min.

Atazanavir/Ritonavir (ATV/r) or Atazanavir/Cobicistat (ATV/c)

Efficacy in Clinical Trials:

The CASTLE study compared once-daily ATV/r (300/100 mg) with twice-daily LPV/r (400/100 mg), each in combination with TDF/FTC. In this open-label, noninferiority study, the two regimens showed similar virologic and CD4 responses at 96 weeks.112

The ACTG A5202 study compared open-label ATV/r and EFV, each given in combination with placebo-controlled TDF/FTC or ABC/3TC. Efficacy was similar in the ATV/r and EFV groups.91 In a separate analysis, women assigned to receive ATV/r were found to have a higher risk of virologic failure than women assigned to receive EFV or men assigned to receive ATV/r.113

In a study comparing ATV/r plus TDF/FTC to EVG/c/TDF/FTC, virologic suppression rates through 144 weeks were similar in the two groups.80 A phase 3 clinical trial of 575 women evaluated EVG/c plus FTC/TDF versus ATV/r plus FTC/TDF.9 At week 48, the virologic suppression rate in the EVG/c arm was superior to the ATV/r arm. Nineteen women in the PI arm discontinued therapy because of adverse events, compared to five women in the INSTI arm.

In ACTG A5257, a significantly higher proportion of patients in the ATV/r arm discontinued randomized treatment because of adverse events, mostly for elevated indirect bilirubin/jaundice or gastrointestinal toxicities. Lipid changes in participants in the ATV/r and DRV/r arms were similar. BMD decreased to a greater extent in participants in the ATV/r and DRV/r arms than in participants in the RAL arm.7

In the Gilead Study 114, all patients received TDF/FTC and ATV, and were randomized to receive either RTV or COBI as PK enhancers. Both RTV and COBI were given as a separate tablet with matching placebos.114 Through 144 weeks, the percentage of patients who achieved virologic suppression was similar in both study arms. The percentage of treatment-discontinuing adverse events and changes in serum creatinine and indirect bilirubin levels were comparable.115

In a phase 3 trial, 499 ART-naive women were randomized to either ATV/r plus TDF/FTC or DTG/ABC/3TC. At 48 weeks, DTG was found to be noninferior to ATV/r in rate of virologic suppression (<50 copies/mL) and fewer drug-related adverse events occurred in the DTG arm.72

Adverse Effects:

The main adverse effect associated with ATV/c or ATV/r is reversible indirect hyperbilirubinemia, with or without jaundice or scleral icterus, but without concomitant hepatic transaminase elevations. The risk for treatment-limiting indirect hyperbilirubinemia is greatest for patients who carry two UGT1A1 decreased-function alleles.116

Nephrolithiasis,117-119 nephrotoxicity,15 and cholelithiasis120 have also been reported in patients who received ATV, with or without RTV.

Both ATV/c and ATV/r can cause gastrointestinal side effects, including diarrhea.

Other Factors and Considerations:

ATV/c and ATV/r are dosed once daily and with food.

ATV requires acidic gastric pH for dissolution. As a result, concomitant use of drugs that raise gastric pH (e.g., antacids, H2 antagonists, and particularly proton pump inhibitors) may impair absorption of ATV. Table 18a provides recommendations for use of ATV/c or ATV/r with these agents.

ATV/c and ATV/r are potent CYP3A4 inhibitors and may have significant interactions with other medications that are metabolized through this same pathway (see Drug Interactions).

Large observational cohort studies found an association between some PIs (DRV/r, FPV, IDV, and LPV/r) and an increased risk of cardiovascular events, while this was not seen with ATV.12-14,106 Another study of an observational cohort of predominantly male participants found a lower rate of CV events in participants receiving ATV-containing regimens compared with participants receiving other regimens.16 Further study is needed.

The Panel’s Recommendations:

On the basis of clinical trial safety and efficacy data, the Panel classifies ATV/r and ATV/c plus TAF/FTC (BII) or TDF/FTC (BI) as Recommended Initial Regimens in Certain Clinical Situations.

ATV/r or ATV/c may be used with ABC/3TC in patients whose pre-ART HIV RNA <100,000 copies/mL (CI for ATV/r and CIII for ATV/c).

ATV/c plus TDF/FTC is not recommended for patients with CrCl <70 mL/min, whereas ATV/c plus TAF/FTC is not recommended for patients with CrCl <30 mL/min.

Other Antiretroviral Regimens for Initial Therapy When Abacavir, Tenofovir Alafenamide, and Tenofovir Disoproxil Fumarate Cannot Be Used

All currently Recommended ARV regimens consist of two NRTIs plus a third active drug. This strategy, however, may not be possible or optimal in all patients. In some situations, it may be necessary to avoid ABC, TAF, and TDF, such as in the case of a patient who is HLA-B*5701–positive or at high risk of cardiovascular disease and with significant renal impairment. Based on these concerns, several clinical studies have evaluated strategies using initial regimens that avoid two NRTIs or the NRTI drug class altogether. Clinicians should refer to HBV/HIV Coinfection for guidance on treatment of patients with HBV infection when TAF or TDF cannot be used as part of the ARV regimen.

Strategies with Good Supporting Evidence

Darunavir/Ritonavir plus Raltegravir (DRV/r plus RAL)

In the NEAT/ANRS 143 study, 805 treatment-naive participants were randomized to receive either twice-daily RAL or once-daily TDF/FTC, both with DRV/r (800/100 mg once daily). At week 96, DRV/r plus RAL was noninferior to DRV/r plus TDF/FTC based on the primary endpoint of proportion of patients with virologic or clinical failure. Among those with baseline CD4 count <200 cells/mm3, however, there were more failures in the two-drug arm; a trend towards more failure was also observed for those with pretreatment HIV RNA ≥100,000 copies/mL.121 High rates of virologic failure in patients with HIV RNA >100,000 copies/mL were also seen in two smaller studies of DRV/r plus RAL.122,123

On the basis of these study results, the Panel recommends that DRV/r plus RAL be considered for use only in patients with HIV RNA <100,000 copies/uL and CD4 counts >200 cells/mm3, and only in those patients who cannot take ABC, TAF, or TDF (CI).

Lopinavir/Ritonavir plus Lamivudine (LPV/r plus 3TC)

In the GARDEL study, 426 ART-naive patients were randomized to receive twice-daily LPV/r plus either open-label 3TC (twice daily) or two NRTIs selected by the study investigators. At 48 weeks, a similar number of patients in each arm had HIV RNA <50 copies/mL, meeting the study’s noninferiority criteria. The LPV/r plus 3TC regimen was better tolerated than the LPV/r plus two NRTI regimen.124

This regimen is used infrequently given the requirement of twice-daily dosing, the relatively high pill burden (a total of 5–6 tablets per day), and the side effect profile of LPV/r. In view of the above limitations, the Panel recommends that LPV/r plus 3TC be considered for use only in patients who cannot take ABC, TAF, or TDF and in whom other alternatives cannot be used (CI).

Selected Strategies That Are Under Evaluation and Not Yet Recommended

Several other treatment regimens for ART-naive patients who cannot use ABC, TAF, and TDF are currently under investigation. As the current data supporting these regimens are limited to single-arm studies or interim analyses of ongoing trials, these regimens cannot yet be recommended. However, some experts may consider these regimens when a patient cannot safely receive ABC, TAF, or TDF. If these treatment strategies are used, patients should be closely monitored to assure viral suppression is achieved and maintained. Two selected strategies are listed below.

The ACTG A5353 trial evaluated this same regimen in a single-arm trial that included ART-naive participants with a baseline HIV RNA of up to 500,000 copies/mL and no genotypic NRTI, INSTI, or PI resistance. The trial enrolled 120 participants; 37 (30.8%) participants had a baseline HIV RNA >100,000 copies/mL. At week 24, 90% of participants had HIV RNA <50 copies/mL; there were similar response rates in participants with baseline HIV RNA >100,000 copies/mL and ≤100,000 copies/mL (89% and 90%, respectively). Three participants experienced virologic failure, all of whom had suboptimal adherence (one developed an integrase gene-associated mutation).127

Two phase 3 trials (GEMINI 1 and 2) comparing DTG plus 3TC to a three-drug regimen of DTG plus TDF/FTC in treatment-naive people with HIV are currently ongoing.

Darunavir/ritonavir plus Lamivudine (DRV/r plus 3TC)

In the ANDES trial, 145 participants were randomized 1:1 to receive either open-label dual therapy with DRV/r plus 3TC or triple therapy with DRV/r plus 3TC/TDF. The median baseline HIV RNA was 4.5 log10 copies, and 24% of subjects had HIV RNA >100,000 copies/mL. The trial is still ongoing, but an intention-to-treat snapshot analysis performed at week 24 showed that 71/75 (95%) subjects in the dual-therapy arm and 68/70 (97%) subjects in the triple-therapy arm achieved HIV RNA <400 copies/mL. By week 24, four subjects in the dual-therapy arm and one subject in the triple-therapy arm had discontinued treatment for reasons other than virologic failure. Virologic failure was documented in one subject in the triple-therapy arm. The investigators intend to enroll an additional 190 patients to power the study for a noninferiority assessment at the primary (week 48) virologic endpoint.128

May cause life-threatening HSRs in patients positive for the HLA-B*5701 allele. As a result, HLA-B*5701 testing is required before use.

In the ACTG 5202 study, patients with baseline HIV RNA ≥100,000 copies/mL showed inferior virologic responses when ABC/3TC was given with EFV or ATV/r as opposed to TDF/FTC. This difference was not seen when ABC/3TC was used in combination with DTG.

ABC use has been associated with CV disease and cardiac events in some, but not all, observational studies.

TAF/FTC

Coformulated with EVG/c or RPV

Active against HBV; a recommended dual-NRTI option for patients with HIV/HBV coinfection

Smaller decline in renal function, less proteinuria, and smaller reductions in BMD than after initiation of TDF/FTC

Approved for patients with eGFR ≥30 mL/min

TDF is associated with lower lipid levels than TAF, perhaps because TDF results in higher plasma levels of tenofovir, which lowers lipids.

TDF/FTC

Coformulated with EFV, EVG/c, and RPV as STRs

Active against HBV; a recommended dual-NRTI option for patients with HIV/HBV coinfection

Better virologic responses than with ABC/3TC in patients with baseline viral load ≥100,000 copies/mL when combined with ATV/r or EFV

Osteomalacia has been reported as a consequence of proximal tubulopathy.

Decreases BMD more than other NRTI combinations

INSTI

DTG

Higher barrier to resistance than EVG or RAL

Coformulated with ABC and 3TC

No food requirement

No CYP3A4 interactions

Favorable lipid profile

Oral absorption of DTG can be reduced by simultaneous administration with drugs containing polyvalent cations (e.g., Al, Ca, or Mg-containing antacids or supplements, or multivitamin tablets with minerals). See dosing recommendations in Table 18d.

Depression and suicidal ideation (rare; usually in patients with pre-existing psychiatric conditions)

EVG/c

Coformulated with TDF/FTC or TAF/FTC

Compared with ATV/r, causes smaller increases in total and LDL cholesterol

EVG/c/TDF/FTC is only recommended for patients with baseline CrCl ≥70 mL/min; this regimen should be discontinued if CrCl decreases to <50 mL/min.

COBI is a potent CYP3A4 inhibitor, which can result in significant interactions with CYP3A substrates.

Oral absorption of EVG can be reduced by simultaneous administration with drugs containing polyvalent cations (e.g., Al, Ca, or Mg-containing antacids or supplements, or multivitamin tablets with minerals). See dosing recommendations in Table 18d.

Increases in creatine kinase, myopathy, and rhabdomyolysis have been reported.

Rare cases of severe HSRs (including SJS and TEN) have been reported.

Higher pill burden than other INSTI-based regimens

No fixed-dose combination formulation

Oral absorption of RAL can be reduced by simultaneous administration with drugs containing polyvalent cations (e.g., Al, Ca, or Mg-containing antacids or supplements, or multivitamin tablets with minerals). See dosing recommendations in Table 18d.

Use with H2 antagonists or antacids with caution (see Table 18a for detailed dosing information).

PIs

ATV/c
orATV/r

Higher genetic barrier to resistance than NNRTIs, EVG, and RAL

PI resistance at the time of treatment failure uncommon with PK-enhanced PIs

ATV/c and ATV/r have similar virologic activity and toxicity profiles

Observational cohort studies have found an association between some PIs (DRV, LPV/r, FPV, IDV) and an increased risk of CV events, while this has not been seen with ATV. Further study is needed. See text for discussion.

Commonly causes indirect hyperbilirubinemia, which may manifest as scleral icterus or jaundice

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